Molecular mechanism of the bitter taste of HIV/AIDS drugs and its inhibition

HIV/AIDS药物苦味及其抑制的分子机制

• 批准号: 10548006
• 负责人: MENG CUI
• 金额: $ 19.63万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10548006
• 关键词: AIDS/HIV problem; Adherence; Anti-HIV Agents; Binding Sites; Biochemical; Biological Assay; Child; Childhood; Complex; Computer Models; Deglutition; Disease; Docking; Drug Design; Drug Modelings; Drug resistance; Formulation; Goals; Health; Homology Modeling; Human; Infant; Lead; Life; Liquid substance; Lopinavir; Lopinavir/Ritonavir; Masks; Medicine; Modeling; Molecular; Mutagenesis; Organic Synthesis; Outcome; Patients; Pharmaceutical Preparations; Receptor Activation; Reporting; Research; Research Proposals; Resistance development; Structural Models; Structure; Taste Buds; Taste Perception; Testing; Visual; base; chemical synthesis; cheminformatics; dosage; experimental study; high throughput screening; improved; lead optimization; liquid formulation; molecular dynamics; molecular modeling; novel; pediatric human immunodeficiency virus; pill; predictive modeling; receptor; release of sequestered calcium ion into cytoplasm; simulation; small molecule inhibitor; success; viral resistance; virtual

Project Summary: The goal of this research proposal is to understand the molecular basis of blocking bitter taste for HIV/AIDS drugs so that their often unpleasant bitter taste can be eliminated. Some drugs have a strong bitter taste, which makes it a challenging task for patients to take them, especially for infants and young children. Because many children cannot swallow pills, pediatric medicines usually come in liquid or syrup form, which frequently taste bitter and is very difficult to mask, even in flavored liquid formulations. It has been reported that when children refuse to take the bitter-tasting HIV/AIDS drugs, and do not get the proper dosage of their drugs, they can develop resistance to the drugs, which has serious consequences for their health. Therefore, there is a need to develop bitter taste blockers to mask the unpleasant taste of HIV/AIDS drugs. Understanding the mechanism of bitter-tasting drug-induced TAS2R receptor activation is likely to lead to discovering bitter taste blockers, which could be used to mask the unpleasant taste of HIV/AIDS drugs. In this proposal, we have developed testable models of the HIV/AIDS drug- TAS2R receptors by computational approaches and our plan is to test them experimentally. Moreover, using structure-based drug design and organic synthesis we aim to discover novel human TAS2R specific blockers to mask the unpleasant bitter taste of different HIV/AIDS drugs.

项目摘要： 这项研究计划的目标是了解阻断苦味的分子基础， 艾滋病毒/艾滋病药物，使其往往令人不快的苦味可以消除。有些药物有 强烈的苦味，这使得患者服用它们是一项具有挑战性的任务，特别是对于 婴幼儿。由于许多儿童不能吞咽药片， 通常以液体或糖浆的形式出现，其通常尝起来是苦的并且非常难以掩盖， 甚至在调味液体制剂中也是如此。据报道，当儿童拒绝服用 艾滋病病毒/艾滋病药物的味道不好，而且没有得到适当的药物剂量，他们可以发展 对药物产生抗药性，对他们的健康造成严重后果。因此有 需要开发苦味阻断剂来掩盖艾滋病毒/艾滋病药物的不良味道。 了解苦味药物诱导的TAS 2 R受体激活的机制可能是 导致发现苦味阻滞剂，这可以用来掩盖不愉快的味道， 艾滋病毒/艾滋病药物。在这项提案中，我们开发了艾滋病毒/艾滋病药物的可测试模型- TAS 2 R受体的计算方法，我们的计划是测试他们的实验。 此外，利用基于结构的药物设计和有机合成，我们的目标是发现新的 人TAS 2 R特异性阻断剂来掩盖不同HIV/AIDS药物的令人不快的苦味。